tbuckley/cabot-search huggingface dataset:
Abstract 504: Membrane-associated heat shock protein mHsp70 is involved in cancer cell invasion and tumor recurrence in malignant brain tumors
Authors: Maxim Shevtsov, Ruslana Tagaeva, Natalia Yudintceva, Danila Bobkov, Darya Goncharova, Alexander Kim, Evgeniy Fedorov, Anastasia Nechaeva, Anastasia Mihrina, Anna Patruhina, Vyacheslav Fedorov, Konstantin Samochernykh
Journal: Cancer Research (2022)

Abstract Heat shock proteins (HSPs) constitute a large family of highly conserved proteins acting as molecular chaperones that play a key role in intracellular proteostasis, regulation of apoptosis, and protection from various stress factors (including hypoxia, thermal stress, oxidative stress). Apart from their intracellular localization, members of different HSPs families such as Hsp70 have been found to be localized on the plasma membrane of malignantly transformed cells, including multiforme glioblastoma (GBM). However, the role of the membrane-bound mHsp70 has not yet been elucidated in the pathophysiology of GBM. We have assessed the mHsp70 expression in biopsies obtained from neuro-oncological patients employing inverted confocal microscopy (Leica Microsystems) and CellVoyager CQ1 Benchtop High-Content Analysis System (Yokogawa). Live-cell imaging of the patient-derived biopsy revealed the increased cellular density of mHsp70-positive tumor cells particularly in the tissue along the tumor-brain margin (biopsy was derived 3 mm from contrast-enhancing margin and also within hyperintense FLAIR). Time-lapse analysis of the tumor sample further demonstrated the migration of mHsp70-positive cells into the surrounding culture medium. Subsequent high-powered multiplex immunofluorescence analysis (Akoya Biosystems Inc.) confirmed markedly increased single-cell infiltration of mHsp70(+) tumor cells (that were also co-immunofluorescently stained for SOX2, Nestin, and Oct4) in the normal brain tissues. In conclusion, expression of mHsp70 on the plasma membrane of tumor cells corresponds to the highly invasive potential of the GBM cells and recurrence of these tumors in neuro-oncological patients. This research was funded by the Ministry of Science and Higher Education of the Russian Federation (Agreement № 075-15-2020-901). Citation Format: Maxim Shevtsov, Ruslana Tagaeva, Natalia Yudintceva, Danila Bobkov, Darya Goncharova, Alexander Kim, Evgeniy Fedorov, Anastasia Nechaeva, Anastasia Mihrina, Anna Patruhina, Vyacheslav Fedorov, Konstantin Samochernykh. Membrane-associated heat shock protein mHsp70 is involved in cancer cell invasion and tumor recurrence in malignant brain tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 504.
Characterization of acne associated with upadacitinib treatment in patients with moderate-to-severe atopic dermatitis: A post hoc integrated analysis of 3 phase 3 randomized, double-blind, placebo-controlled trials
Authors: Pedro Mendes-Bastos, Barry Ladizinski, Emma Guttman-Yassky, Ping Jiang, John Liu, Vimal H. Prajapati, Eric L. Simpson, Namita Vigna, Henrique D. Teixeira, Sebastien Barbarot
Journal: Journal of the American Academy of Dermatology (2022)
Abstract 589: Discovery of NTX-001, a potent Cbl-b inhibitor with antitumor activity in syngeneic models
Authors: Fred Csibi-Levin, Silvana Leit, David L. Laughton, Tom Baker, Suzanne L. Jacques, Beth Browning, Angela V. Toms, Samantha Garside, Simon D'Archivio, Katarzyna Kopycka, Xiaohua Zhu, Allan M. Jordan, Stuart Thomson, Christine Loh, Peter Tummino, David N. Ciccone
Journal: Cancer Research (2022)

Abstract Introduction: Casitas B-lineage lymphoma b (Cbl-b), a RING finger E3 ligase and a member of a highly conserved family of Cbl proteins, catalyzes the ubiquitination of substrate proteins to regulate multiple signaling events in a variety of cell types, including immune cells. In T cells, Cbl-b negatively regulates adaptive immune system signaling by establishing the threshold for the activation of antigen receptors. Additionally, Cbl-b regulates the function of other immune cell types, including NK cells, dendritic cells (DC) and monocytes. Cbl-b deficient T cells no longer require a costimulatory signal to be fully activated. Cbl-b KO mice spontaneously reject tumors via an enhanced immune response. Taken together, these findings point to Cbl-b inhibitors as having the potential to be highly efficacious immuno-oncology agents. Experimental Procedures: A structure-based drug design approach was used to identify potent inhibitors of Cbl-b. Biochemical and cellular binding assays, a cellular NFAT-luciferase reporter assay, as well as primary in vitro human and mouse T cell activation assays measuring IL-2 production were used to profile inhibitor compounds. In vivo activity of Cb-b inhibitors was evaluated using an anti-CD3 mouse model and a CT-26 syngeneic mouse model Results: Cbl-b inhibitor NTX-001 potently binds to Cbl-b, preventing Cbl-b phosphorylation and binding to E2. In cells, NTX-001 treatment results in enhanced phosphorylation of ZAP-70, a protein proximal to the TCR and reported to be a direct substrate of Cbl-b. Additionally, inhibition of Cbl-b potently enhances cytokine secretion from primary human and mouse T cells. In vivo, an increase in cytokines and T cell activation markers was observed after a single dose of NTX-001. Repeated dosing of NTX-001 showed dose-dependent anti-tumor activity in the colorectal CT-26 syngeneic model. Conclusions: NTX-001 is a potent Cbl-b inhibitor that demonstrated strong T cell activation and anti-tumor activity in a syngeneic tumor model. These data support Cbl-b inhibitors as a promising therapeutic opportunity for cancer treatment. Citation Format: Fred Csibi-Levin, Silvana Leit, David L. Laughton, Tom Baker, Suzanne L. Jacques, Beth Browning, Angela V. Toms, Samantha Garside, Simon D'Archivio, Katarzyna Kopycka, Xiaohua Zhu, Allan M. Jordan, Stuart Thomson, Christine Loh, Peter Tummino, David N. Ciccone. Discovery of NTX-001, a potent Cbl-b inhibitor with antitumor activity in syngeneic models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 589.
Abstract 5545: Intestinal toxicity to CTLA-4 blockade driven by IL-6 and myeloid infiltration
Authors: Yifan Zhou, Yusra B. Medik, Bhakti Patel, Daniel B. Zamler, Sijie Chen, Thomas Chapman, Sarah Schneider, Rachel L. Babcock, Taylor T. Chrisikos, Laura M. Kahn, Allison M. Dyevoich, Elizabeth M. Park, Alexandria P. Cogdill, Daniel H. Johnson, Sarah B. Johnson, Khalida M. Wani, Debora A. Ledesma, Courtney W. Hudgens, Jingjing Wang, Md Abdul Wadud Khan, Aron Y. Joon, Weiyi Peng, Haiyan S. Li, Reetakshi Arora, Ximing Tang, Maria Gabriela Raso, Xuegong Zhang, Wai Chin Foo, Michael T. Tetzlaff, Gretchen E. Diehl, Karen Clise-Dwyer, Elizabeth M. Whitley, Matthew M. Gubin, James P. Allison, Patrick Hwu, Nadim J. Ajami, Adi Diab, Jennifer A. Wargo, Stephanie S. Watowich
Journal: Cancer Research (2022)

Abstract Immunotherapies such as anti-CTLA-4 immune checkpoint blockade (ICB) have revolutionized cancer treatment, yet quality of life and continuation of therapy can be constrained by off-target tissue damage or immune-related adverse events (irAEs). At present, there is limited understanding of irAE mechanisms, hampering development of approaches to mitigate their damage. We addressed this problem by generating animal models of intestinal irAE. Our results show that disruption of homeostatic immunity by genetic predisposition to intestinal inflammation or acute gastrointestinal infection sensitizes mice to anti-CTLA-4-mediated intestinal toxicity. Inflammation-prone mice treated with anti-CTLA-4 showed neutrophil accumulation, systemic interleukin-6 (IL-6) release, and dysbiosis. Significantly, IL-6 blockade combined with antibiotic treatment improved anti-CTLA-4 therapeutic efficacy and reduced intestinal irAEs. Immune signatures were validated in biopsies from patients who developed colitis during ICB, supporting the utility of our models. This study provides new pre-clinical models, mechanistic insight into irAEs, and potential approaches to enhance ICB efficacy while mitigating irAEs. Citation Format: Yifan Zhou, Yusra B. Medik, Bhakti Patel, Daniel B. Zamler, Sijie Chen, Thomas Chapman, Sarah Schneider, Rachel L. Babcock, Taylor T. Chrisikos, Laura M. Kahn, Allison M. Dyevoich, Elizabeth M. Park, Alexandria P. Cogdill, Daniel H. Johnson, Sarah B. Johnson, Khalida M. Wani, Debora A. Ledesma, Courtney W. Hudgens, Jingjing Wang, Md Abdul Wadud Khan, Aron Y. Joon, Weiyi Peng, Haiyan S. Li, Reetakshi Arora, Ximing Tang, Maria Gabriela Raso, Xuegong Zhang, Wai Chin Foo, Michael T. Tetzlaff, Gretchen E. Diehl, Karen Clise-Dwyer, Elizabeth M. Whitley, Matthew M. Gubin, James P. Allison, Patrick Hwu, Nadim J. Ajami, Adi Diab, Jennifer A. Wargo, Stephanie S. Watowich. Intestinal toxicity to CTLA-4 blockade driven by IL-6 and myeloid infiltration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5545.
Abstract 2984: ARHGAP17, a Cdc42-specific GAP, localizes to invadopodia and regulates their turnover as part of an ARHGAP17/Cdc42/CIP4 complex
Authors: Gabriel Kreider-Letterman, Abel Castillo, Agustin Rabino, Eike K. Mahlandt, Joachim Goedhart, Silvia Goicoechea, Rafael Garcia-Mata
Journal: Cancer Research (2022)

Abstract One of the hallmarks of aggressive cancer is its ability to invade into surrounding tissues and metastasize. Many invasive cancers form invadopodia, which are protrusive, degradative structures that are regulated by the Rho family of GTPases. Rho GTPases commonly have aberrant activity in invasive cancers caused by changes in their upstream regulators: RhoGEFs and RhoGAPs. We have identified the RhoGAP ARHGAP17 (RICH1/NADRIN) as a negative regulator of invadopodia in triple negative breast cancer. Using confocal and STORM super-resolution microscopy techniques, we show that ARHGAP17 localizes to the regulatory ring surrounding invadopodia where it acts to promote disassembly by decreasing invadopodia lifetime through the inactivation of the Rho GTPase Cdc42. We further support these results in live cells by using a new localization-based Cdc42 biosensor, which reveals that ARHGAP17 suppresses Cdc42 activity specifically at the invadopodia ring. We have also identified the Cdc42 effector CIP4 as part of a complex with ARHGAP17 and Cdc42 that we propose is key in the regulation of invadopodia. Finally, using spheroid and inverse invasion assays, we show that the invadopodia phenotype correlates with increased invasive properties. In conclusion, we have identified ARHGAP17 as a key regulator of invadopodia and invasion in triple negative breast cancer by localizing to invadopodia and inactivating Cdc42 as part of a complex with CIP4. In future studies, we will further characterize the molecular mechanisms that regulate the ARHGAP17/Cdc42/CIP4 complex and their function during invadopodia formation. Citation Format: Gabriel Kreider-Letterman, Abel Castillo, Agustin Rabino, Eike K. Mahlandt, Joachim Goedhart, Silvia Goicoechea, Rafael Garcia-Mata. ARHGAP17, a Cdc42-specific GAP, localizes to invadopodia and regulates their turnover as part of an ARHGAP17/Cdc42/CIP4 complex [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2984.
Abstract 5407: Targeting NRF2 using specific inhibitor brusatol sensitized esophageal adenocarcinoma cells to cisplatin through inducing ferroptosis
Authors: Dunfa Peng, Tianling Hu, Lei Chen, Heng Lu, Shoumin Zhu, Wael El-Rifai
Journal: Cancer Research (2022)

Abstract Background: The incidence rate of the esophageal adenocarcinoma (EAC) has increased rapidly among men during the past four decades in the USA and western countries while the 5 year survival rate is still below 20%. Traditional chemotherapy is still the main stream strategy in treatment of EAC patients. However, chemo-resistance usually develops that finally leads to failure of treatments. NFE2-related factor 2 (NRF2) is the master regulator of cellular anti-oxidant properties that maintains cell viability and cellular homeostasis. Overexpression of NRF2 in human cancers are associated with drug-resistance and poor prognosis. Methods and Results: NRF2 protein levels are higher in several EAC cell lines, as compared to BE cell lines (CPA, BAR10T) and normal esophageal squamous cell lines, using Western blot analysis. We confirmed NRF2 overexpression in primary EAC samples, using immunohistochemistry on a tissue microarray that contained 76 EACs. Brusatol is an NRF2 specific inhibitor originated from natural plant. Administration of Brusatol in EAC cells significantly inhibited NRF2 ARE luciferase activity and reduced gene expression of NRF2 target genes such as GR, HO1, GSTM2, GPX3 and GPX4, resulting in a significant increase in cellular ROS levels, which were further increased by treatment with CDDP with subsequent increase in cancer cell death. Further investigation revealed that Brusatol significantly increased lipid peroxidation levels as detected by immunofluorescence assay and flow cytometry and resulted in significant ferroptosis, in particular in combination with CDDP treatments. We confirmed that Brusatol in combination with CDDP significantly suppressed tumor growth in a xenografting mice model. Conclusion: Constitutive overexpression of NRF2 in EAC cells favors tumor cell survival and drug resistance. NRF2 specific inhibitor may synergize with traditional chemotherapeutic drugs by inducing lipid peroxidation and ferroptosis in EAC. Citation Format: Dunfa Peng, Tianling Hu, Lei Chen, Heng Lu, Shoumin Zhu, Wael El-Rifai. Targeting NRF2 using specific inhibitor brusatol sensitized esophageal adenocarcinoma cells to cisplatin through inducing ferroptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5407.
Abstract 4071: Utilizing colforsin as a novel therapeutic for high grade serous ovarian cancer treatment
Authors: Matthew Knarr, Hunter Reavis, Marilyn Mitchell, Ronny Drapkin
Journal: Cancer Research (2022)

Abstract Epithelial ovarian cancer (EOC) is currently the deadliest gynecological cancer with approximately 20,000 new cases and 15,000 deaths per year in the United States. Ovarian cancer can be stratified into distinct subtypes of which high-grade serous ovarian cancer (HGSOC) comprises 90% of all cases. The majority of HGSOC patients are diagnosed with late-stage disease and have a poor prognosis with a 5-year survival rate of less than 30%. Thus, there is a critical need to develop novel therapeutic strategies to improve patient treatment and survival outcomes. Our lab has recently discovered that the small molecule colforsin has potent anti-cancer properties when used to treat HGSOC in vitro and in vivo. Colforsin is a water-soluble derivative of forskolin, and acts as an activator of cAMP signaling via direct binding and activation of adenylyl cyclase. It is currently in clinical use for treatment of conditions such as glaucoma, diabetes, and liver fibrosis. This makes colforsin a prime candidate for drug repurposing to treat ovarian cancer. Our data show that colforsin can induce cell cycle arrest and cell death in established HGSOC cell line models in vitro. We have also found that colforsin can inhibit tumor growth and tumor burden in an intraperitoneal model of HGSOC using HEYA8 cells. In addition, we have also found that colforsin acts synergistically with cisplatin to cause HGSOC cell death. Taken together, our data show that colforsin has potential as a new therapeutic tool to aid in HGSOC treatment in combination with existing therapies. Citation Format: Matthew Knarr, Hunter Reavis, Marilyn Mitchell, Ronny Drapkin. Utilizing colforsin as a novel therapeutic for high grade serous ovarian cancer treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4071.
Viral Shedding Kinetics and Transmission of Emerging SARS-CoV-2 Variants—Critical Components of Study Design
Authors: Camden D. Gowler, Prabasaj Paul, Sujan C. Reddy
Journal: JAMA Network Open (2022)

Jiwon Jung, MD; Ji Yeun Kim, PhD; Heedo Park, MS; Sunghee Park, MD; Joon Seo Lim, PhD; So Yun Lim, MD; Seongman Bae, MD; Young-Ju Lim, MSN; Eun Ok Kim, MPH; Jineui Kim, MS; Man-Seong Park, PhD; Sung-Han Kim, MD
Abstract 415: The characterization of <i>in vitro</i> models demonstrating a significant delay of acquired resistance to ulixertinib (ERK1/2)
Authors: Deborah Knoerzer, Anupama Reddy, David Sorrell, Caroline M. Emery
Journal: Cancer Research (2022)

Abstract Ulixertinib (BVD-523) is a first-in-class small molecule inhibitor of ERK1/2 currently being investigated in several oncology clinical trials, both as a single agent and in combination with other anti-cancer therapeutics. Clinical acquired resistance has been described by others for numerous efficacious small molecule agents. Relevant to the MAPK pathway, emergence of resistance to BRAF and MEK inhibitors limits their clinical efficacy. In vitro models of ulixertinib resistance were generated in an endeavor to characterize and predict potential clinical mechanisms of resistance and guide rational combination therapies. The BRAF-V600E mutant melanoma cell line, A375, was cultured in progressively increasing concentrations of ulixertinib or other MAPK pathway inhibitors (dabrafenib and/or trametinib). Drug-resistant A375 clones were readily obtained following growth in high concentrations of dabrafenib or trametinib. In contrast, developing resistance to ulixertinib proved challenging. Eventually, ulixertinib resistant clones emerged and demonstrated varying degrees of cross-resistance to other MAPK pathway inhibitors and displayed bell-shaped dose-response curves indicative of drug addiction for optimal proliferation. To elucidate potential mechanisms of resistance, Reverse Phase Protein Array profiling of 306 proteins was performed on parental A375 and ulixertinib-resistant clones following treatment with ulixertinib at varying concentrations and treatment times. Principal component analysis revealed clustering of resistant clones by ulixertinib treatment conditions (concentrations and duration). Differences between parental A375 and ulixertinib resistant clones were revealed, including components of MAPK, HER2, and autophagy markers. This work begins to tease out potential mechanisms of resistance to ulixertinib and guide potential combination partners that could circumvent acquired resistance. Citation Format: Deborah Knoerzer, Anupama Reddy, David Sorrell, Caroline M. Emery. The characterization of in vitro models demonstrating a significant delay of acquired resistance to ulixertinib (ERK1/2) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 415.
Longitudinal Changes in Arterial Stiffness and Heart Rate Variability in Youth-Onset Type 1 Versus Type 2 Diabetes: The SEARCH for Diabetes in Youth Study
Authors: Amy S. Shah, Scott Isom, Ralph D’Agostino, Lawrence M. Dolan, Dana Dabelea, Giuseppina Imperatore, Amy Mottl, Eva Lustigova, Catherine Pihoker, Santica Marcovina, Elaine M. Urbina
Journal: Diabetes Care (2022)

OBJECTIVE We compared arterial stiffness and heart rate variability (HRV) over time by diabetes type and determined the risk factors associated with worsening arterial stiffness and HRV in young adults with youth-onset diabetes. RESEARCH DESIGN AND METHODS Arterial stiffness (pulse wave velocity, augmentation index) and six indices of heart rate variability were measured twice, 4.5 years apart, among participants with either youth-onset type 1 or type 2 diabetes in the SEARCH for Diabetes in Youth study. Multivariable linear regression models were used to assess risk factors associated with arterial stiffness and HRV at follow-up. RESULTS Of 1,159 participants studied, 949 had type 1 diabetes (mean age 17.1 ± 4.7 years, 60.3% non-Hispanic White, 55% female) and 210 had type 2 diabetes (mean age 22.1 ± 3.5 years, 23.8% non-Hispanic White, 71% female) at initial assessment when diabetes duration was 7.9 years (both groups). Participants with type 2 versus type 1 diabetes had greater arterial stiffness and more abnormalities in HRV at initial and follow-up assessment and a greater change over time (all P &amp;lt; 0.05). Risk factors associated with worse arterial stiffness and HRV at follow-up in both types of diabetes included higher blood pressure, hemoglobin A1c, waist circumference, and triglycerides over time and longer diabetes duration. CONCLUSIONS Arterial stiffness and HRV worsened over time with greater changes among participants with type 2 versus type 1 diabetes and among those with features of the metabolic syndrome. The risk factor profile documents potentially modifiable pathways to prevent or limit cardiovascular complications in young adults with youth-onset diabetes.
Combination Antidepressant Therapy vs Monotherapy—Further Considerations
Authors: Klaus Munkholm, Asger Sand Paludan-Müller
Journal: JAMA Psychiatry (2022)

To the Editor Henssler et al1 reported the results of a systematic review and meta-analysis comparing combination antidepressant therapy with antidepressant monotherapy for the treatment of depression. Some aspects of the review should be considered when interpreting the results.
Pilot Program for Veterans With PTSD to Train Service Dogs
Authors: Melissa Suran
Journal: JAMA (2022)

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